title: Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors.
abstract: Tetrabenazine (TBZ) ((±)-1) and dihydrotetrabenazines (DHTBZ) are potent inhibitors of VMAT2. Herein, a practical chemical resolution of (±)-1 and stereoselective synthesis of all eight DHTBZ stereoisomers are described. The result of VMAT2 binding assay revealed that (+)-1 (Ki=4.47 nM) was 8000-fold more potent than (-)-1 (Ki=36,400 nM). Among all eight DHTBZ stereoisomers, (2R,3R,11bR)-DHTBZ ((+)-2: Ki=3.96 nM) showed the greatest affinity for VMAT2. The (3R,11bR)-configuration appeared to play a key role for VMAT2 binding. In summary, (+)-1, (+)-2, and their derivatives warrant further studies in order to develop more potent and safer drugs for the treatment of chorea associated with Huntington's disease and other hyperkinetic disorders.
authors.affiliation: Center for Drug Discovery, College of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Zhangyu
authors.initials: Z
authors.lastname: Yao
authors.forename: Xueying
authors.initials: X
authors.lastname: Wei
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wu
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Katz
authors.forename: Theresa
authors.initials: T
authors.lastname: Kopajtic
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
authors.forename: Hongbin
authors.initials: H
authors.lastname: Sun
mesh_terms: D000818:Animals; D008297:Male; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors*
chemical_list: C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; C032811:dihydrotetrabenazine; D013747:Tetrabenazine